4-Amino-1-hydroxybutylidene-1,1-bisphosphonic acid (ABP), and salts thereof, is a new antihypercalcemic agent effective in the treatment or prevention of diseases involving hypercalcemia of pregnancy, Paget's disease and osteoporosis.
Methods for preparing ABP are known in the art and are disclosed in U.S. Pat. No. 4,407,761 to Henkel and U.S. Pat. No. 4,922,007 to G. R. Kiecykowski et al (assigned to Merck & Co., Inc.). However, these methods employ the use of toxic and environmentally dangerous phosphorus trichloride and phosphorous acid in their procedures. Newer methods which do not employ these particularly hazardous and toxic reagents are constantly being searched for.
The articles, J. Org. Chem. Vol. 36, No. 24, pp. 3843-45 (1971) and J. Med. Chem. 1987, Vol. 30, pp. 1426-1433, describe general methods of preparation of tetramethylalkyl-1-hydroxy-1,1-diphosphonates but do not specifically describe the preparation of omega-amino-1-hydroxyalkyl diphosphonates.
The use of the phthaloyl protecting group in amino acid chemistry is well known, e.g., J. Med. Chem. 1979, vol. 22, No. 11, pp. 1399-1402, but there is no specific teaching as to their possible use in preparing omega-amino-1-hydroalkyl diphosphonates.